Mendelian randomization study adds to 'burgeoning evidence'

In yet another confirmation of the negative cardiometabolic impact of obesity, researchers detailed a causal effect for high body mass index (BMI) on heart and diabetes risks through Mendelian randomization (MR) analysis.

The "genetically instrumented" measure of high BMI exposure -- calculated based on 93 single-nucleotide polymorphisms associated with BMI in prior genome-wide association studies -- was associated with the following risks (odds ratios given per standard deviation higher BMI):

Hypertension (OR 1.64, 95% CI 1.48-1.83)

Coronary heart disease (CHD; OR 1.35, 95% CI 1.09-1.69)

Type 2 diabetes (OR 2.53, 95% CI 2.04-3.13)

Systolic blood pressure (β 1.65 mm Hg, 95% CI 0.78-2.52 mm Hg)

Diastolic blood pressure (β 1.37 mm Hg, 95% CI 0.88-1.85 mm Hg)

However, there were no associations with stroke, Donald Lyall, PhD, of the University of Glasgow, and colleagues reported online in JAMA Cardiology.

"The main advantage of an MR approach is that certain types of study bias can be minimized," the team noted. "Because DNA is stable and randomly inherited, which helps to mitigate errors from reverse causality and confounding, genetic variation can be used as a proxy for lifetime BMI to overcome limitations such as reverse causality and confounding, a process that hampers observational analyses of obesity and its consequences."

Together with other similar MR findings, the results have "relevance for public health policies in many countries with increasing obesity levels," the researchers concluded.

Christopher J. O'Donnell, MD, MPH, of the VA Boston Healthcare System and Brigham and Women's Hospital in Boston, in an accompanying editor's note, pointed to a study limitation in the use of cross-sectional rather than prospective association analysis: "From a preventive cardiology perspective, the MR study of Lyall et al refocuses attention on, and strengthens the body of literature for, a 'causal' connection of BMI with increasing blood pressure, diabetes, and CHD," O'Donnell concluded. "Nevertheless, further research is needed to expand our understanding of [the] mechanism from molecular genetic and/or interventional clinical studies."

The research received funding from the Welsh Assembly Government and the British Heart Foundation.

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